Catalan Institute of Oncology (ICO), Girona, Catalonia, Spain.
Cell Cycle. 2010 Sep 15;9(18):3807-14. Epub 2010 Sep 25.
The sole overexpression of pivotal regulators of the embryonic Epithelial-Mesenchymal Transition (EMT) genetic program ("EMT status") may be sufficient to efficiently drive the ontogeny of the breast cancer stem cell molecular signature independently of changes in EMT functioning ("EMT phenotype"). Using basal-like breast cancer models naturally enriched in either CD44(pos)CD24(low/neg) or CD44(pos)CD24(pos) tumor-initiating cell populations we herein illustrate that non-cytotoxic concentrations of the anti-diabetic drug metformin efficiently impedes the ontogeny of generating the stem cell phenotype by transcriptionally repressing the stem cell property EMT. Metformin treatment dynamically regulated the CD44(pos)CD24(neg/low) breast cancer stem cell immunophenotype, transcriptionally reprogrammed cells through decreased expression of key drivers of the EMT machinery including the transcription factors ZEB1, TWIST1 and SNAI2 (Slug) and the pleiotrophic cytokines TGFβs, and lastly impeded the propensity of breast cancer stem cells to form multicellular "microtumors" in non-adherent and non-differentiating conditions (i.e., "mammospheres"). These findings, altogether, provide strong motivation for the continued molecular understanding and clinical development of metformin as a non-toxic therapeutic aimed to interdict the breast cancer stem cell phenotype by targeting EMT, a molecular process that is central to the ontogenesis of the breast cancer stem cell molecular signature.
胚胎上皮-间充质转化（EMT）基因程序关键调控因子的单一过表达（“EMT 状态”）可能足以有效地驱动乳腺癌干细胞分子特征的发生，而与 EMT 功能的变化（“EMT 表型”）无关。使用自然富含 CD44(pos)CD24(low/neg)或 CD44(pos)CD24(pos)肿瘤起始细胞群体的基底样乳腺癌模型，我们在此说明，非细胞毒性浓度的抗糖尿病药物二甲双胍通过转录抑制干细胞特性 EMT 有效地阻碍了产生干细胞表型的发生。二甲双胍治疗动态调节 CD44(pos)CD24(neg/low)乳腺癌干细胞免疫表型，通过降低 EMT 机制的关键驱动因子的表达，包括转录因子 ZEB1、TWIST1 和 SNAI2（Slug）以及多效细胞因子 TGFβs，重新编程细胞，最后阻碍乳腺癌干细胞在非粘附和非分化条件下形成多细胞“微肿瘤”（即“乳腺球体”）的倾向。这些发现为进一步深入了解二甲双胍作为一种非毒性治疗药物的分子机制提供了有力的依据，旨在通过靶向 EMT 来抑制乳腺癌干细胞表型，EMT 是乳腺癌干细胞分子特征发生的核心分子过程。
